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Published on 1 September 2007

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Cytostatic drugs and quality assurance in exposure assessment

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Roberta Turci
MSc

Research Chemist

Claudio Minoia
MSc

Laboratory Supervisor

Laboratory for Environmental and Toxicological Testing
Salvatore Maugeri Foundation
Pavia
Italy

E: roberta.turci@fsm.it

Occupational exposure to antineoplastic drugs (ADs) has been recognised as a potential health hazard since the 1970s.(1,2) Hospital personnel preparing and administering therapies may be exposed to ADs by inhalation of aerosols, drug droplets and dust, or by direct skin contact. Inadvertent ingestion is also possible, as are accidental events such as injuries from sharps. And ­handling, storage, transport and disposal of these drugs are tasks which may also lead to exposure.

Specific guidelines have been published in ­several countries.(3–7) Their goal is to keep the ­exposure level as low as reasonably achievable (the so-called ALARA principle). This approach is based on implemen­tation of handling procedures, use of specialised and personal protective equipment, and training and education of personnel.

Biological and environmental monitoring are essential tools for the collection of adequate ­exposure data and for effective intervention. To assess exposure levels and contamination levels in the workplace, new methods have been ­developed and several surveys have been carried out in healthcare settings. Nevertheless, a recent literature review of the most significant methods has revealed a lack of detail concerning quality assurance.(8) In recent years the Salvatore Maugeri Foundation ­Laboratory for Environmental and Toxicological Testing in Pavia, Italy, has developed and validated a number of ­analytical methods for the determination of several drugs in environmental and biological samples.

Our main objective has been and remains to develop methods suitable for routine monitoring – that is, methods that are as precise as possible, cost- and time-effective, and validated, including measurement of uncertainty.

Validation studies rely on the determination of overall method performance parameters:(9)

  • Confirmation of identity.
  • Selectivity/specificity.
  • Limit of detection.
  • Limit of quantification.
  • Working and linear ranges.
  • Accuracy: precision (repeatability and reproducibility) and trueness.
  • Measurement uncertainty.
  • Sensitivity.
  • Ruggedness (or robustness).
  • Recovery.

Each laboratory should decide what degree of ­validation is required for a particular ­analytical ­problem – also taking financial constraints into account, ­particularly when the method is going to be used on a routine basis. To judge whether or not a method is suitable for its intended purpose, it is ­necessary to include the required level of uncertainty, expressed either as a standard uncertainty or as expanded uncertainty.(10) In practice, the uncertainty regarding the result may arise from many sources. It is therefore very important to look closely at all possible sources of uncertainty (including sampling, matrix effects and interferences, environmental conditions and approximations in the measurement method and procedure). Each source of uncertainty is then treated separately to obtain the ­contribution from that source (uncertainty component). The total uncertainty, termed “combined standard uncertainty”, is a standard deviation obtained by ­combining all the uncertainty components. In ­analytical ­chemistry, an expanded uncertainty is often used, which provides an interval within which the value of the measurand is believed to lie with a higher level of confidence.

The main results of our work are presented in a series of papers.(11–18) For the most important anti­neoplastic agents the instrumental technique used, precision (CV%), trueness, limit of ­detection (LOD), limit of quantitation (LOQ) and ­combined relative uncertainty at a given concentration level are listed. It is noteworthy that use of high-performance instrumentation such as HPLC-MS/MS allows simul­taneous analysis of different drugs with low LODs.(16,18) The evaluation of uncertainty further increases the confidence that can be placed on the results. Note that a method is ­conventionally ­considered reliable when the total uncertainty is less than 30%. Our results comply with this rule, making the methods at issue suitable for application to exposure assessment.

After gaining consistent analytical results, the next step is interpreting them. In this respect, it could be useful to have a sort of reference table for each drug and for each kind of matrix, which could ensure a uniform interpretation of the analytical results across the countries.

In addition, the practice should be to keep on record any analysis (along with an updated list of exposed personnel), the frequency and duration of exposure, and reports of incidents, injuries or any equipment failure. This database is essential for future reference in order to assess any possible relationship between occupational exposure and adverse health effects.

It is still true that the percentage of positive ­samples has significantly decreased in recent years, but in fact there is no safe exposure level above zero.(8,19) Nevertheless, despite the large amount of effort and all the progress made, contamination still occurs.

What is actually required here is a ­comprehensive approach: analytical aspects cannot be ­separated from monitoring strategy and from education and training. That is why personnel must take their share of responsibility. Education and ­training is ­undoubtedly a key component of the overall ­system.

Last but not least, existing guidelines call for economically feasible tests. However, a mandatory monitoring system involves costs and this, along with the necessary technical requirements, may be a limiting factor in implementation.

References
1
. Falck K, Grohn P, Sorsa M, et al. Mutagenicity in urine of nurses handling cytostatic drugs. Lancet 1979;i:1250-1.
2. International Agency for Research on Cancer. Complete list of agents, mixtures and exposures evaluated and their classification. Lyon: IARC; 2002. Available at: www.iarc.fr
3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm 2006;63:1172-93.
4. Eitel A, Scherrer M, Kümmerer K. Handling cystotatic drugs: a practical guide. Munich: International Society of Oncology Pharmacy Practitioners; 2005. Available at: www.uniklinik-freiburg.de/iuk/live/informationsmaterial/zytoengl.pdf
5. Kaijser GP, Underberg, WJ, Beijnen JH. The risks of handling cytotoxic drugs II: recommendations for working with cytotoxic drugs. Pharm World Sci 1990;12(6):228-35.
6. US Occupational Safety and Health Administration. OSHA technical manual. Washington DC; OSHA: 2004;6;2. Available at: www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html#3
7. US National Institute for Occupational Safety and Health. Preventing occupational exposure to antineoplastic and other hazardous drugs in healthcare settings. NIOSH Publication 2004-165. Atlanta GA: NIOSH; 2004.
8. Turci R, Sottani C, Spagnoli G, et al. Biological and environmental monitoring of hospital personnel exposed to antineoplastic agents: a review of analytical methods. J Chromatogr B 2003;789:169-209.
9. EURACHEM. The fitness for purpose of analytical methods: a laboratory guide to method validation and related topics. Teddington UK: EURACHEM; 1998. Available at: www.eurachem.org/guides/valid.pdf
10. Ellison SLR, et al. Quantifying uncertainty in analytical measurement. Teddington UK: EURACHEM/CITAC; 2000. Available at: www.eurachem.org/guides/QUAM2000-1.pdf
11. Sottani C, Tranfo G, Faranda P, et al. Highly sensitive high-performance liquid chromatography/selective reaction monitoring mass spectrometry method for the determination of cyclophosphamide and ifosfamide in urine of health care workers exposed to antineoplastic agents. Rapid Commun Mass Spectrom 2005;19(19):2794-800.
12. Minoia C, Turci R, Sottani C, et al. Application of high performance liquid chromatography/tandem mass spectrometry in the environmental and biological monitoring of health care personnel occupationally exposed to cyclophosphamide and ifosfamide. Rapid Commun Mass Spectrom 1998;12:1485-93.
13. Turci R, Micoli G, Minoia C. Determination of methotrexate in environmental samples by solid phase extraction and high performance liquid chromatography: ultraviolet or tandem mass spectrometry detection? Rapid Commun Mass Spectrom 2000;14:685-91.
14. Micoli G, Turci R, Arpellini M, Minoia C. Determination of 5-fluorouracil in environmental samples by solid-phase extraction and high performance liquid chromatography with ultraviolet detection. J Chromatogr B 2001;750:25-32.
15. Sottani C, Zucchetti M, Zaffaroni M, et al. Validated procedure for simultaneous trace level determination of the anti-cancer agent gemcitabine and its metabolite in human urine by high-performance liquid chromatography with tandem mass spectrometry. Rapid Commun Mass Spectrom 2004;18(10):1017-23.
16. Sottani C, Tranfo G, Bettinelli M, et al. Trace determination of anthracyclines in urine: a new high-performance liquid chromatography/tandem mass spectrometry method for assessing exposure of hospital personnel. Rapid Commun Mass Spectrom 2004;18(20):2426-36.
17. Spezia S, Bocca B, Forte G, et al. Comparison of inductively coupled plasma mass spectrometry techniques in the determination of platinum in urine: quadrupole vs sector field. Rapid Commun Mass Spectrom 2005;19:1551-6.



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